Document made available under
`Patent Cooperation Treaty (PCT)
`
`the
`
`International application number: PCT/US2006/033672
`
`International filing date:
`
`28 August 2006 (28.08.2006)
`
`Document type:
`
`Certified copy of priority document
`
`Document details:
`
`Country/Office: US
`Number:
`60/711,950
`Filing date:
`26 August 2005 (26.08.2005)
`
`Date of receipt at the International Bureau: 20 November 2006 (20.11 .2006)
`
`Remark: Priority document submjtted or transmitted to the International Bureau in
`compliance with Rule 17. l(a) or (b)
`
`World Intellectual Property Organization (WIPO) - Geneva, Switzerland
`Organisation Mondiale de la Propriete Intellectuelle (OMPI) - Geneve, Suisse
`
`

`

`l J Nff'F.:[) SL\TE:S l)U'AIH'M:ENT OF <:OMM.ERCE
`
`liuitcd States Patent and Trndcm11rk Ollicc
`
`November 07, 2006
`
`THIS IS TO CERTIFY THAT ANNEXED HERETO IS A TRUE COPY FROM
`THE RECORDS OF THE UNITED STA TES PA TENT AND TRADEMARK
`OFFICE OF THOSE PAPERS OF THE BELOW IDENTIFIED PATENT
`APPLICATION THAT MET THE REQUIREMENTS TO BE GRANTED A
`FILING DA TE.
`
`APPLICATION NUMBER: 60/711,950
`FILING DA TE: August 26, 2005
`RELATED PCT APPLICATION NUMBER: PCT/US06/33672
`
`THE COUNTRY CODE AND NUMBER OF YOUR PRIORITY
`APPLICATION, TO BE USED FOR FILING ABROAD UNDER THE PARIS
`CONVENTION, IS US60/711,950
`
`( \,rtifiNI hy
`
`Under Seci·etary of Commerce
`for lntdketual l'ro1>crtr
`and Director of tile lJni1·c1I Sia1e~
`1-'otcnt nnd Tnidt'mark Ofl1ce
`
`

`

`0 t-o
`Cl.: l()
`PTO/SB/16 (07-051 ~ O')
`Approved for use through 7/31/2006. 0MB 0651-0032. ::> T"'"
`U.S. Palen! and Tradernar1< Office: U.S. DEPARTMENT OF COMMERCE
`T"'"
`Underlhe Paperworl< Reduction Act or 1995, no persons are required to respond to a a,lleclion of infoonaton uness tt displays a vali:l 0MB conlrel number.· ~ !:::::
`~g
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`.....
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`Expr ess Ma il L abel No. EV 664382224 US
`-------- ------------------
`
`INVENTOR(S)
`Family Name or Surname
`
`Given Name (first and middle [if anyJ )
`
`Residence
`(Citv and either State or Foreign Country}
`Sunnyvale, California
`YEOMANS
`David C.
`White Bear Lake, Minnesota
`FREY II
`WilliamH.
`Daniel I.
`Palo Alto, California
`JACOBS
`separately numbered sheets attached hereto
`Additional inventors are being named on the
`TITLE OF THE INVENTION (500 characters max)
`THERAPY PROCEDURE FOR DRUG DELIVERY FOR TRIGEMINAL PAIN
`
`Direct all correspondence to:
`
`CORRESPONDENCE ADDRESS
`
`25226
`
`I
`
`0The address corresponding to Customer Number. I
`(cid:143)
`
`OR
`
`Firm or
`Individual Name
`
`Address
`
`City
`Country
`
`I state
`[Zip
`!Email
`[Telephone
`ENCLOSED APPLl<;:ATION PARTS (check all that apply)
`
`0Application Data Sheet. See 37 CFR 1.76 (3 pages) 0 CD(s), Number of CDs
`0 Other (specify) I Return Receipt Postcard
`
`0 Specification Number of Pages
`
`46
`
`0 Drawing(s) Number of Sheets
`
`I
`
`I
`
`1
`Application Size Fee: Filing Fee of$200 (S 100 for small entity). If the specification and drawings exceed 100 sheets of paper, an
`application size fee due, which is $250 ($125 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41(a)(1)(G)
`and 37 CFR 1.161s).
`METHOD OF PAYMENT OF FILING FEES AND APPLICATION SIZE FEE FOR THIS PROVISIONAL APPLICATION FOR PATENT
`TOTAL FEE
`AMOUNT\$)
`100.00
`
`0 Applicant claims small entity status. See 37 CFR 1.27.
`
`0 A check or money order is enclosed to cover the filing fee and application size fee (if applicable).
`0 Payment by credit card. Fonm PT0-2038 is attached.
`
`I
`
`0
`
`The Director is hereby authorized to charge the fifing fee and application size fee (if applicable) or credit any overpayment to Deposit
`03-1952
`
`A duplicative copy of this form is enclosed for fee processing.
`
`Account Number:
`
`The invention was made by an agency of the Unijed States Government or under a conlra<:I with an agency of the United States Government
`
`0No." D Yes. the name of the U.S. Go,emment agency
`
`and the Government contract number are:
`
`SIGNATURE
`
`TYPED or PRINTED NAME
`
`Diane Pardi
`TELEPHONE _ ____ ____,(..._65_0 ... )_8_1_3-_5_6_36 ___ __ _
`Docket Number.
`USE ONLY FOR RLING A PROVISIONAL APPLJCA T/ON FOR PATENT
`[Number 1 of 1 ]
`
`Date
`REGISTRATION
`NO.
`/If appropriate)
`
`August26,2005
`
`56,824
`
`286003023500
`
`I hereby certify that this correspondence is being deposited
`in an envelope addressed to: Commissioner for Patents,
`
`e U.S. Postal Service as Express Mail. Airt:>ill No. EV 664382224 US.
`Box 1450. /;.lexandrit_A 22313-1450, on the dale shown below.
`
`Daled: August 26, 2005
`
`Signature:-r-~b,l,(J:lc:.!:;JA=""'-'""----=-~....:...~-<Georgina Matos)
`
`pa-1005151
`
`

`

`THERAPY PROCEDURE FOR DRUG DELIVERY FOR TRIGEMINAL PAIN
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001)
`
`Not applicable.
`
`STATEMENT REGARDING.FEDERALLY SPONSORED
`
`RESEARCH OR DEVELOPMENT
`
`[0002)
`
`Not applicable.
`
`TECHNICAL FIELD
`
`[0003)
`
`The present invention relates generally to methods and compositions for the treatment
`
`of pain. More specifically, the present invention relates to methods for the treatment or prevention
`
`of trigeminal nerve-associated procedural, acute and chronic pain by administration and targeted
`
`delivery of analgesic agents to the trigeminal nerve system resulting in localized pain relief with
`
`minimal untoward central nervous system effects or systemic side effects.
`
`BACKGROUND OF THE INVENTION
`
`[0004]
`
`Pain is experienced when the free nerve endings which constitute the pain receptors
`
`in the skin as well as in certain internal tissues are subjected to mechanical, thermal, chemical or
`
`other noxious stimuli. The pain receptors (nociceptors) can transmit signals along afferent neurons
`
`into the central nervous system and then to the brain. The causes of pain can include inflammation,
`
`injury, disease, muscle spasm and the onset of a neuropathic event or syndrome. Ineffectively
`
`treated pain can be devastating to the person experiencing it by limiting function, reducing mobility;(cid:173)
`
`complicating sleep, and dramatically interfering with the quality oflife.
`
`(0005]
`
`The trigeminal sensory nerves (afferents) innervate and transmit to the brain most of
`
`the sensory signals from the face and anterior head. Pain involving the trigeminal nerve and
`
`ganglion arises in many different medical situations and presents unique problems to pain therapists
`
`and doctors. Chronic pain due to syndromes such as trigeminal neuralgia, atypical facial pain,
`
`

`

`anesthesia dolorosa, post-herpetic neuralgia, cancer of the head and neck, migraine headaches, and
`
`temporomandibular joint pain are examples of very different pain syndromes that all involve the
`
`trigeminal system and which present clinical challenges that are peculiar to this nerve distribution.
`In addition to chronic pain states, there are clinical situations where facial and head pain is
`
`associated with acute trauma such as an abscessed tooth, a headache or a direct injury to the face
`
`and/or head such as a laceration or a burn. Further, medical procedures such as common dental
`
`work and facial plastic and/or cosmetic surgery may elicit considerable pain, as well as discomfort
`
`and anxiety.
`
`[0006]
`
`Among syndromes associated with facial pain is Trigeminal neuralgia, also called "tic
`
`duloreaux" which is among the most common facial pain syndromes. Trigeminal neuralgia usually
`
`begins after the age of 40, is slightly more common in women and has an incidence of approximately
`
`4-5 per 100,000 persons (K.horami and Totah, 2001). The primary symptom oftrigeminal neuralgia
`
`is the sudden onset of severe, sharp facial pain, usually without warning. The quick bursts of pain
`
`are described as "lightening bolt-like", "machine gun-like" or "electric shock-like". The pain is
`
`generally on one side of the face and is spasmodic, coming in short bursts lasting a few seconds
`
`which may repeat many times over the course of a day. Trigeminal neuralgia can involve one or
`
`more branches of the trigeminal nerve and the causes are varied. Pharmacologic treatments include
`
`anti-seizure medications such as carbamazepine (Tegretol, Carbatrol), phenytoin (Dilantin),
`
`clonazepam (Klonopin), gabapentin (Neurontin), and lamtrignine (Lamictal), tricyclic
`
`antidepressants such as amitriptyline (Elavil) and muscle relaxants such as baclofen. The treatments
`
`generally have limited efficacy and many patients eventually undergo an invasive procedure. The
`
`procedural interventions often involve the direct manipulation of the trigeminal ganglion and include
`
`microvascular decompression, alcohol injection aimed at destroying pain fibers, glycerol injection
`
`aimed at selectively destroy pain-transmitting fibers, percutaneous radiofrequency rhizotomy, pulse
`.
`:,,,,,--
`radio frequency and gamma-knife. The pain relief from these procedures can be successful in a
`
`percentage of these patients, but the relief can be short-lived and often facial pain returns.
`
`Significant procedural pain and long term morbidity may also be associated with such treatments.
`
`· (0007)
`
`Atypical Facial Pain (ATFP) is a syndrome encompassing a wide group of facial pain
`
`problems. ATFP can have many different causes but the symptoms are all similar. Facial pain,
`
`often described as burning, aching or cramping, occurs on ~me side of the face, often in the region of
`
`2
`
`

`

`the trigeminal nerve and can extend into the upper neck or back of the scalp. Although rarely as
`
`severe as trigeminal neuralgia, facial pain is continuous t:or ATFP patients, with few, if any periods
`
`of remission. Some studies propose that ATFP is an early form of trigeminal neuralgia, but there is
`
`no agreement at this time. Drug treatments for ATFP are similar to what is prescribed for trigeminal
`
`neuralgia including anti-seizu.re medications and tricyclic antidepressants with limited effectiveness.
`
`(0008]
`
`Anesthesia dolorosa is one of the most dreaded complications of neurosurgery and is
`
`considered to be non-reversible. The two main symptoms of anesthesia dolorosa are facial
`
`numbness (much like the numbness from a dental anesthetic injection) and constant pain. The pain
`
`is usually burning, pulling or stabbing but can also include a sharp, stinging, shooting or electrical
`
`component. Pressure and "heaviness" can also be part of the pain symptoms and often there is eye
`
`pain. Cold can increase the feeling of numbness sometimes making the face feel frozen. Anesthesia
`
`dolorosa occurs when the trigeminal nerve is damaged by surgery, physical trauma or as a
`
`complication of surgery to correct a condition such as trigeminal neuralgia. Topical treatments with
`
`capsaicin are used to help manage the pain and discomfort, while topical clonidine has been tested in
`
`a few cases but no single treatment has been found that resolves all of the pain of this condition.
`
`(0009]
`
`Post-herpetic neuralgia is pain that remains after the rash from shingles (herpes
`
`zoster) has healed. Shingles is an infection of the nerves caused by the varicella-zoster virus, which
`
`is the same virus that causes chickenpox. About one-third of the people who get shingles will get
`
`post herpetic neuralgia. The pain of post herpetic neuralgia may be constant, stabbing, aching, or
`
`burning and can last for months to years after the shingles outbreak.
`
`(0010)
`
`It is predicted that approximately 65,000 Americans will be diagnosed with head and
`
`neck cancers this year, this represents about 3% of all cancers diagnosed in the United States
`
`(American Cancer Society). Close to 60% of head and neck cancer patients report long-term pain
`
`with up to 25% claiming moderate or severe pain (List and Stracks (2000) Curr Opin Oneal.,
`
`12:215-20). The trigeminal nerves and ganglion are likely to mediate most of the head and facial
`
`pain in these patients and sometimes are directly affected by the cancerous growth. The
`
`recommended treatment for most cancer patients with mild to severe pain is opioid therapy such as
`
`hydrocodone, codeine, oxycodone, morphine, fentanyl and hydromorphone. Opioid therapy has a(cid:173)
`
`multitude of problems including systemic effects away from the site of pain stimulation.
`
`Furthermore, opioids are highly addictive and patients build up tolerance to the drugs quickly
`
`resulting in higher and higher doses being administered.
`
`3
`
`

`

`Migraine headaches affect more than 23 million people in the United States. The
`(0011]
`typical migraine headache is· throbbing or pulsatile, it builds up over a period of 1-2 hours and lasts
`
`from several hours to a whole day. Pain intensity is moderate to severe and can be debilitating and
`
`·often causes nausea and vomiting. Of particular interest to clinicians who study migraine headaches
`
`is the superior trigeminal division (the ophathalmic division). This division innervates the forehead,
`
`eyebrow, eyelid, anterior scalp, nose and contents of the orbit thus giving an explanation for the pain
`
`localization along with the visual aura that is common with migraine headaches. Common
`
`treatments for migraine headaches include beta-blockers such as propranolol (Inderal) and Atenolol,
`
`tricyclic antidepressants, ergotamines, anti-seizure drugs a~d calcium channel blockers. Many of
`
`these drugs have systemic side effects and limited effectiveness.
`
`(0012]
`
`Acute facial pain can arise in patients undergoing common dental procedures such as
`
`tooth extraction, root canal surgery and surgery for dental implants and dental prostheses. Acute
`
`dental pain can also arise from dental/gingival disease, other conditions such as an abscessed tooth
`
`or a bacterial infection or injury, that arise separately from planned dental procedures. Most dentists
`
`use topical anesthetics such as Benzocaine, Eugenol and forms of Xylocaine to numb various areas
`
`for minor procedures or before injection of a local anesthetic. For most procedures a dentist will
`
`inject a local anesthetic such as Lidocaine, Xylocaine and Marcaine to create a nerve block at or
`
`around the site where dental work needs to be done. Local anesthetics numb the area where they are
`
`injected and eliminate the acute pain of most procedures. In addition to the pain of administration,
`
`another main disadvantage of local anesthetics, especially for routine dental procedures, is that
`
`numbness and loss of sensation in the facial region will usually last for several hours after the dental
`
`procedure is finished.
`
`(0013]
`
`Facial plastic surgery is becoming a very common procedure with several million
`
`procedures done in the United States each year. The procedures range from necessary repair of
`
`damage such as lacerations or broken bones to elective cosmetic surgeries such as face lifts,
`
`rhinoplasties, skin rejuvenation, etc. For many of these procedures local anesthetics are used (the
`
`patients are not under general anesthetic) and as with dental procedures, the local anesthetics can be
`
`painful to administer and include the problem of lingering numbness lasting for hours after the
`
`procedure is finished. In addition, depending on the surgery performed, patients experience varying
`
`levels of post-operative pain after the anesthetic wears off.
`
`4
`
`

`

`[0014)
`
`Pain treatment of almost any type usually includes some form of analgesic agent or
`
`drug. Analgesic drugs are usually classified into three groups: non-opioid drugs, opioid drugs, and
`
`co-analgesic drugs, also known as adjuvants. Non-opioid analgesic drugs include acetaminophen
`
`and non-steroidal anti-inflammatory drugs or NSAIDs. Opioid drugs, sometimes referred to as
`
`"narcotics", include natural substances such as morphine, and semi-synthetic and synthetic
`
`substances. Co-analgesic medications are drugs that have a primary use other than pain relief, but
`
`also help produce analgesia for some painful conditions.
`
`[0015]
`
`Opioid drugs are commonly used to relieve pain however their usefulness is limited
`
`by the tolerance and dependence that normally develops on chronic treatment. Opioid drugs such as
`
`morphine can be addictive and can have central nervous system-mediated side effects such as
`
`respiratory and cardiac depressions and drowsiness. Additionally, opioid drugs suffer from frequent
`
`side effects such as nausea, vomiting and constipation.
`
`[0016)
`
`Therapeutic drugs are delivered by a number of routes including, for example, oral,
`
`intravenous injection, intramuscular injection and subcutaneous injection. For patients suffering
`
`procedural, acute or chronic pain associated with the trigeminal nerve, one of the main problems
`
`with convention drug delivery with analgesic agents is the lack of localized pain relief due to
`
`systemic distribution of the agent. Often larger dosages need to be administered to achieve an
`
`effective concentration of the drug at a desired site. With higher doses of an analgesic agent, there is
`
`the additional problem of limited efficacy relative to the increase in undesired side effects due to the
`
`systemic distribution of the agent. Treatments consisting of localized but invasive interventions
`
`directly to the trigeminal nerve have a significant disadvantage due to the lack of selectivity and/or
`
`reversibility of the intervention and the fact that these procedures can, by·themselves, cause
`
`additional facial nerve problems including anesthesia doloroso, persistent numbness and nerve
`
`deafferentation. An additional problem with conventional treatments for trigeminal nerve-associated
`
`pain, especially with invasive procedures, is the high level of skill, training and equipment required
`
`by the medical team which can make treatment expensive and impractical for widespread use.
`
`(0017)
`
`Intranasal administration has been used for systemic delivery of several therapeutic
`
`agents, for example, insulin, thryrotropin-releasing hormone, and vasopressin. In addition, using an
`
`intranasal or other mucosa! route for systemic delivery of a therapeutic agent allows for ease of
`
`administration and the ability to bypass intestinal degradation and first pass hepatic metabolism of
`
`the therapeutic agent. However, there are times when it is desirable to not have systemic distribution
`
`5
`
`

`

`of a therapeutic agent or to have a therapeutic agent targeted to a localized or regional area. For
`
`examples, intranasal drug delivery has been used to bypass the blood-brain barrier and deliver
`
`substances to the central nervous system (CNS) and the brain. It has been demonstrated that large
`
`molecules such as polypeptides, peptides, oligonucleotides or DNA plasmids can be delivered
`
`directly to the CNS via specific uptake routes within the nose such as the axonal and perineural
`
`vascular/lymphatic pathways of the olfactory and trigeminal nerves (Frey II (2002) Drug Delivery
`
`Technology, 2:46-49; Thome et al. (2004) Neuroscience, 127:481-496). Thus while there is
`
`evidence that various therapeutic agents can be delivered to the brain by an intranasal route and that
`
`the agents may travel along perineural pathways, there is no known method utilizing these pathways
`
`to specifically target the trigeminal nerve system for localized or regional analgesia in individuals
`
`suffering from trigeminal nerve-associated pain.
`
`(0018)
`
`Despite a wide range of medical treatments, trigeminaJ nerve-associated pain, in
`
`many different forms and situations, continues to affect millions of people. Thus new methods for
`
`treating an individual for trigeminal nerve-associated pain are needed to directly target the trigeminal.
`
`nerve system with analgesic agents and deliver analgesia to facial or head regions with minimal
`
`central nervous system effects or systemic side effects.
`
`BRIEF SUMMARY OF THE INVENTION
`
`(0019)
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`pain, comprising: administering to the individual an effective amount of an analgesic agent wherein
`
`the administration is targeted to the trigeminal nerve system and results predominantly in analgesia
`
`to the facial or head region. Some aspects of the invention include methods wherein the trigeminal
`
`nerve-associated pain is selected from the group consisting of chronic, acute and procedural-related
`
`pain and combinations thereof. In some examples, the chronic pain is selected from the group
`
`consjsting of trigeminal neuralgia, atypical facial pain, anesthesia dolorosa, post-herpetic neuralgia,
`cancer of the head and neck, migraine headaches, and temporomandibular joint pain. In some
`
`examples, the procedural-related pain is pain arising from dental, medical, surgical or cosmetic
`procedures. In yet other examples, the acute pain is pain arising from a laceration, a burn, a broken
`
`bone, an injury, a headache, an abscessed tooth, dental disease, a bacterial infection or a sinus
`
`infection.
`
`6
`
`

`

`(0020)
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`pain, comprising: administering to the individual an effective amount of an analgesic agent wherein
`
`the administration is targeted to the trigeminal nerve system and results predominantly in analgesia
`
`to the facial or head region and wherein the analgesic agent is administered via mucosa! or dermal
`
`admin_istration. In some examples the analgesic agent is administered intranasally. In other
`
`examples the analgesic agent is administered via buccal or sublingual administration. In other
`
`examples the analgesic agent is administered to conjunctiva or other mucosa! tissues around the eye.
`
`In yet other examples the analgesic agent is administered to the skin or dermal surface.
`(0021 I
`pain, comprising: administering to the individual an effective amount of an analgesic agent wherein
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`the administration is targeted to the trigeminal nerve system and results predominantly in analgesia
`
`to the facial or bead region. Some aspects of the invention include methods wherein the analgesic
`
`agent includes, but is not limited to, a peptide, an amino acid, or a polypeptide. In some examples
`
`the analgesic agent is an opioid peptide selected from a group comprising enkephalins, endorphins,
`
`dynorphins, endomorphins, casomorphins, dermorphin, oxytocin and analogues and derivatives
`thereof. In some examples the analgesic agent is a peptide which inhibits peptidergic enzymes. In
`
`other examples the peptide is a peptidergic receptor agonist. In yet other examples the peptide is a
`
`peptidergic receptor antagonist. In further examples the analgesic agent is an antibody directed
`
`against proalgesic antigens such as endothelin, nerve growth factor, vasoactive intestinal polypeptide
`
`(VIP) or pituitary adenylate cyclase-activating polypeptide (P ACAP). In some examples the
`
`analgesic agent is an antibody directed against calcitonin gene-related peptide (CGRP),
`
`cholecystokinin (CCK), Substance P or galanin.
`
`(0022)
`
`Some aspects of the invention include methods wherein the analgesic agent is
`
`administered as a pharmaceutical composition. Accordingly, provided herein are methods for
`
`treating an individual for trigeminal nerve-associated pain, comprising: administering to the
`
`individual an effective amount of a pharmaceutical composition comprising an analgesic agent
`
`wherein the administration is targeted to the trigeminal nerve system and results predominantly in
`
`analgesia to the facial or head region. Some aspects of the invention include methods wherein the
`
`pharmaceutical composition is administered in a dosage form selected from a group comprising a
`
`powder, a liquid, a gel, an ointment, a suspension, a cream or a bioadhesive. Some aspects of the
`
`invention include methods wherein the pharmaceutical composition further comprises a protease
`
`7
`
`

`

`inhibitor, an absorption enhancer, a vasoconstrictor or combinations thereof. In some examples, the
`
`protease inhibitor is selected from a group comprising antipain, arphamenine A and B, benzamidine
`
`HCI, AEBSF, CA-074, calpain inhibitor I and II, calpeptin, pepstatin A, actinonin, amastatin,
`
`bestatin, chloroacetyl-HOLeu-Ala-Gly-NH2, DAPT, diprotin A and B, ebelactone A and B,
`
`foroxymithine, leupeptin, pepstatin A, phosphoramidon, aprotinin, BBi, soybean trypsin inhibitor,
`
`phenylmethylsulfonyl fluoride, E-64, chymostatin, 1, 10-phenanthroline, EDT A and EGT A. In other
`
`examples the absorption enhancer is selected from a group comprising surfactants, bile salts,
`
`bioadhesive agents, phospholipid additives, mixed micelles, liposomes, or caniers, alcohols,
`
`enamines, cationic polymers, NO donor compounds, long-chain amphipathic molecules, small
`
`hydrophobic penetration enhancers; sodium or a salicylic acid derivatives, glycerol esters of
`
`acetoacetic acid, cyclodextrin or beta-cyclodextrin derivatives, medium-chain fatty acids, chelating
`
`agents, amino acids or salts thereof, N-acetylamino acids or salts thereof, mucolytic agents, enzymes
`
`specifically targeted to a selected membrane component, inhibitors of fatty acid synthesis and
`
`inhibitors of cholesterol synthesis.
`
`[0023]
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`pain, comprising: administering to the individual i) an effective amount of a pharmaceutical
`
`composition comprising an analgesic agent wherein the administration is targeted to the trigeminal
`
`nerve system and results predominantly in analgesia to the facial or head region and ii) a
`
`vasoconstrictor wherein administration of the vasoconstrictor reduces systemic distribution of the
`
`analgesic agent. In some examples the vasoconstrictor is selected from the group comprising
`
`phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline
`
`hydrochloride, tramazoline hydrochloride, endothelin-1, endothelin-2, epinephrine, norepinephrine
`
`and angiotensin. In some examples the vasoconstrictor is administered prior to the administration of
`
`the pharmaceutical composition. In other examples the vasoconstrictor is co-administered with the
`
`pharmaceutical composition. In some examples administration of the vasoconstrictor results in a
`
`decreased effective dosage of the analgesic agent.
`
`(0024)
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`pain, comprising: administering to the individual an effective amount of a pharmaceutical
`
`composition comprising an analgesic peptide wherein the peptide is administered by buccal or
`
`sublingual administration to the oral cavity and wherein the peptide preferentially binds to opioid
`
`receptors within the trigeminal nerve system and results predominantly in analgesia to the facial or
`
`8
`
`

`

`head region. Some aspects provide methods for treating an individual for trigeminal nerve(cid:173)
`
`associated pain, comprising: administering to the individual an effective amount of a phannaceutical
`
`composition comprising an analgesic peptide wherein the peptide is administered by transdermal
`
`administration to the skin and wherein the peptide preferentially binds to opioid receptors within the
`
`trigeminal nerve system and results predominantly in analgesia to the facial or head region
`
`[0025)
`
`Provided herein are methods for treating an individual for trigeminal nerve-associated
`
`pain, comprising: administering to the individual an effective amount of a pharmaceutical
`
`composition comprising an analgesic peptide wherein the peptide is administered by intranasal
`
`administration to the nasal cavity and wherein the peptide preferentially binds to opioid receptors
`
`within the trigeminal nerve system and results predominantly in analgesia to the facial or head
`region. In some examples the administration is directed to the inferior two-thirds of the nasal cavity.
`
`In other examples the administration is directed to the inferior two-thirds of the nasal cavity and is
`
`directed away from the olfactory region.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0026]
`
`Figure 1 depicts data demonstrating withdrawal latencies after noxious thermal
`
`stimulation to the ears or hindpaws in a rat model after intranasal administration of met-enkephalin.
`
`Panel A shows baseline and treated withdrawal latencies after thermal stlmulation to the ear. Panel
`
`B shows baseline and treated withdrawal latencies after thermal stimulation to the hindpaw. After
`
`taking baseline withdrawal latencies, rats were intranasally administered 10 nmoles/kg met(cid:173)
`
`enkephalin and withdrawal latencies were retested. Each bar represents the average, across 4
`
`animals, of latencies in response to stimulation at a particular time after the beginning of the set.
`
`Thus, the first white bar in each graph represents responses at the beginning of the baseline testing
`
`set; the first black bar represents responses at approximately five minutes after administering met(cid:173)
`
`enkephalin. Each successive bar represents responses at approximately 15 minutes after the previous
`
`bar.
`
`9
`
`

`

`DETAILED DESCRIPTION OF THE INVENTION
`
`[0027)
`
`As used herein, unless otherwise specified, the term "treatment" or "treating pain"
`
`refers to administration to an individual an agent of interest wherein the agent alleviates or prevents
`
`a pathology for which the subject is being treated. Treatment for trigeminal nerve-associated pain
`
`refers to the alleviation or prevention of trigeminal nerve-associated pain.
`
`[0028)
`
`As used herein, "central nervous system" or "CNS" refers to that part of the nervous
`
`system that consists of the brain and spinal cord. The CNS is one of the two major divisions of the
`
`nervous system. The other is the peripheral nervous system which is outside of the brain and spinal
`
`cord and includes the cranial nerves - of which the trigeminal nerve is a member.
`
`(0029) ·
`
`Although analgesia in the strictest sense is an absence of pain, as used herein,
`
`"analgesia" refers to reduction in the intensity of the pain perceived by an individual without causing
`
`general numbness.
`
`[0030]
`
`As used herein, "analgesia agent", "analgesic agent" or "analgesic" refers to any
`
`biomolecule that alleviates or prevents pain.
`
`[0031)
`
`As used here, "analgesic peptide" refers to any peptide molecule that alleviates or
`
`prevents pain.
`
`[0032]
`
`As used herein, "opioid P,eptide" refers to a peptide having a opioid receptor binding
`
`moiety and the capacity to bind to an opioid receptor. An opioid peptide can be a naturally
`
`occurring endogenous peptide, fragments, analogues or derivatives thereof. An opioid peptide can
`
`also be a non-endogenous peptide, fragments, analogues or derivatives thereof.
`
`[0033]
`
`As used herein, "analogues and derivatives" refers to any peptide analogous to
`
`naturally occurring opioid peptides wherein one or more amino acids within the peptide have been
`
`substituted, deleted, or inserted. The term also refers to any peptide wherein one or more amino
`acids have been modified, for example by chemical modification. In general, the term covers all
`
`peptides which bind to an opioid receptor and exhibit an opioid activity but which may, if desired,
`
`have a different potency or pharmacological profile.
`
`[0034)
`
`As used herein, "acute pain" refers to sudden, severe pain from a specific cause
`
`(injury, infection, inflammation, etc) that lasts a limited time (as opposed to chronic pain). As used
`
`herein "chronic pain" refers to a persistent state of pain whereby the cause of the pain cannot be
`
`easily removed. Chronic pain is often associated w·ith long-term incurable or intractable medical
`
`10
`
`

`

`conditions or diseases. As used herein "procedural pain" refers to pain arising from a medical,
`
`dental or surgical procedure wherein the procedure is usually planned or associated with acute
`
`trauma.
`
`[0035)
`
`As used herein "systemic side effects" include, but are not limited to, cardiovascular
`
`including peripheral vasodilation, reduced peripheral resistance, and inhibition of baroreceptors;
`
`dermatologic including pruritus (itching), flushing and red eyes; gastrointestinal including nausea
`
`and vomiting, decreased gastric motility in stomach, decreased biliary, pancreatic and intestinal
`
`secretions and delays in food digestion in small intestine, diminished peristaltic waves in large
`
`intestine contributing to constipation, epigastric distress or biliary colic in biliary tract; respiratory
`
`including depressed respiratory rate; and urinary including urinary urgency and difficulty with
`
`urination, and perip